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Innate Immunity > Macrophages > Flashcards

Macrophages Flashcards

1
Q

Haematopoiesis is?

A

Haematopietic stem cells found in bone marrow of adults differentiate into various cells

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2
Q

Features of HSCs

A

Sustain blood cells throughout life

Capable of self-renewal

Multipotent - stem cells generate other cells of multiple lineages

Two main lineages generated are lymphoid and myeloid cells

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3
Q

Determining factors for Cells produced by HSC

A

Cellular environment

Transcription factors

Soluble mediators in the environment

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4
Q

How does Pattern Associated Molecular Patterns(PAMPs) help microbe recognition

A

PAMP receptors recognise PAMPs
Works on principle there is difference between cell and pathogenic cells

PAMP also recognised indirectly

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5
Q

Examples of Bacterial PAMPs

A

Cell wall components

Such as LPS and LTA

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6
Q

Examples of viruses PAMPs

A

ssRNA and dsRNA that form part of viral life cycle

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7
Q

Examples of yeast PAMPs

A

Sugars

B-glucans

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8
Q

Examples of helminths PAMPs

A

Sugars e.g Chitin

Proteins

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9
Q

Where are PRRs encoded?

A

Germline encoded in genes for multicellular organisms

Highly abundant in cells of innate immune response
- phagocytes(macrophages neutrophils and dendritic cells)

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10
Q

Where are PRRs located

A

Soluble
Exposed on cell surface
In cytoplasm
In vacuoles

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11
Q

What are Toll Like Receptors

A

Best characterises PRRs

Recognise wide range of pathogens which lead to appropriate signalling and responses

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12
Q

How many TLRs are there

A

10

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13
Q

What is TLR1

Ligand and target microbes

A

Triacyl lipopeptides

Mycobacteria

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14
Q

What is TLR2
Ligand

Target microbes

A

Peptidoglycans - Gram positive bacteria

GPI-linked proteins - Trypanosomes

Lipoproteins - mycobacteria

Zymosan - yeasts and other fungi

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15
Q

What is TLR3 ligand and target microbes

A

dsRNA - Viruses

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16
Q

What is TLR4 ligand and microbes?

A

LPS - Gram-negative bacteria

F-protein - Respiratory Syncytial virua

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17
Q

What is TLR5 ligand and microbe

A

Flagellin - bacteria

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18
Q

What is TLR6 ligand and target microbes

A

Diacyl lipopeptides - mycobacteria

Zymosan- yeast and other fungi

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19
Q

What is TLR7 and TLR8 ligand and target microbes?

A

ssRNA - Viruses

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20
Q

What is TLR9 ligand and target microbes?

A

CpG unmethylated dinucleotides and dinucleotides - Bacterial DNA

Herpesvirus infection - Some herpesviruses

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21
Q

What are the major classes of PRR besides TLR’s and what they bind to?

A

Dectin-1 Receptors binds to B-glucans

Mannose receptor bind to mannose

Scavenger receptor bind to lipids/proteins

22
Q

Major roles of macrophages

A

Pattern recognition
Phagocytosis
Killing infected cells
Cytokines release

Direct both innate and adaptive immune response through secretion of cytokines and chemokines plus antigen presentation to T cells

23
Q

Where do Macrophages derive

Where are macrophages found

A

HSC from myeloid lineage
Myeloid precursor bone marrow cells

Macrophages found in all tissues within body

24
Q

What cells have myeloid precursors

A

Neurtrophils
Monocytes
Macrophages

25
Q

What is role of Monocytes

A

Released into circulation so can enter tissues and replace resident tissue macrophages

26
Q

What control myeloid differentiation

A

Sequential TFs
Soluble mediators
Micro-environmental factors

27
Q

What are tissue resident macrophages?

A

Macrophages that establish in tissue during early embryogenesis to produce resident cells that proliferate

Have different expression patterns that can be analysed by microarray

28
Q

What are DAMPs

A

Damage associated molecular patterns from stressed cells and allow recognition of healthy cells from damaged cells

Usually from contents of damaged cell spilling out.

29
Q

Macrophages integrate a large number of stimuli which result in different types of activation

Why?

A

Enhances effector functions and ensure a directed and appropriated response

30
Q

How does classically activated macrophage work?

A

Tissue macrophage recognises e.g LPS with TLR or IFNy released by cells when they recognise viruses

This causes differentiation of macrophage into a classically activate macrophage

31
Q

How can you recognise a classically activated macrophage?

A

Surface markers and phenotypic features

E.g. Lots of MHC Class II on the surface

Produce many antimicrobials
E.g. Hydrogen peroxide, nitric oxide

Th1 cytokines

IL-6, IL-23 leads to Th17 cells

32
Q

What are wound healing macrophages

What do they do and how

A

Macrophages that cause tissue damage repair

Produce precursors of collagen for tissue
By
Increasing transcription and translation of arginase which will convert to arginine to ornithine a precursor for polyamide an collagen for matrix regeneration

Increase apoptosis

33
Q

What activates Wound healing macrophages

A

Inflammatory cytokines or Th2 cytokines such as IL4

34
Q

How can pathogens skew wound healing macrophages

A

M.tb increases arginase production for survival

35
Q

What are Regulatory Macrophages?

A

For parts like eyes,brain and tested where we do not want excessive inflammatory response to prevent excess damage

Anti-inflammatory Macrophages produce anti-inflammatory cytokines IL-10, TGF-B to calm down response

36
Q

What are Tumor associated macrophages?

And how do they work?

A

Macrophages are hijacked by tumors
Found in tumors

Differentiate to produce environment beneficial for tumour E.g increase VEGF to increase vascularise to tumour cells to encourage growth

Suppress immune response so tumours not killed.

Produce growth factors to encourage tumour development

Macrophage normally indicate poor prognosis for tumours

37
Q

Macrophages recognise pathogen via

A

Directly or opsonic Receptors

38
Q

What is phagocytosis

A

Main mechanism for uptake and destruction of microbes and apoptosis cells

39
Q

Three major steps of macrophage phagocytosis

A

Initial recognition (receptor mediated)

Uptake, signalling and actin-driven cytoskeletal remodelling

Processing-killing, presentation or non inflammatory removal

40
Q

Name pathogens that evade phagocytosis

A

Yersinia, salmonella, clostridium toxins that block Rho-family of GTPases

41
Q

How does uptake via opsonic phagocytosis work?

A

Particles coated in complement or soluble pattern recognition Receptors (MBL, collections,MFG-8) or antibodies

Receptors recognise coated pathogens and phagcytose it

E.g. Binding by FC receptor and zipper hypothesis

42
Q

What are main Fc Receptors?

A

FcyRI( CD64) has high affinity to momomeric IgG

FcyRIIandRIII(CD32 and 16) – low affinity – polymeric IgG

43
Q

Stages of phagocytosis

A

Ligand binding

Activation of phagocytic cell

Engulfment

Internalisation /fusion with lysosomes

44
Q

How does phagosome maturation progress

A

Phagosome matures and gradually acidified via fusion with lysosomes from endocytic pathway

Rab protein 5,7,11 essential for vesicular fusion

Final degradation through generating phagolysosome

Pathogen components either presented on surface to initiate further immune response or degraded in cell

45
Q

What pathogen blocks phagolysosome formation

A

M.tb by inhibiting sphingosine kinase signalling

46
Q

Autophagy how it occurs

And what is it

A

Initiated via starvation or stress from viral infection

Cell packages cut solid contents in double membrane vehicle and delivers to lysosomes for degradation

Growing evidence cells use same machinery against invading microorganism

47
Q

Killing mechanisms of macrophages ?

A

Reactive oxygen species/ reactive nitrogen species

Proteolytic and hydrolytix enzymes -e.g proteases

Antimicrobial peptides

Nutrient deprivation

48
Q

What are antimicrobial peptides?

A

Defensins and cathelicidins

-short peptides, between 12 and 50 aminonacids

Positively charges and bind electrostatically to form multimeric pores killing microbes

Also act as chemoattractants

49
Q

What increases acidity in phagosmal maturation

A

Acidity increased via V-ATPase

50
Q

Name hydrolytic enzymes

A

Lysozymes, cathespin D, lipases

51
Q

What does the deprivation of nutrients macrophage kills mechanism?

A

IDO metabolise tryptophan

Arginase metabolises arginine

Vitamin B12 binding protein and lacroferrin being B12 and iron

Innate Immunity (5 decks)

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